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  • 1
    ISSN: 1432-1041
    Keywords: Antidepressant ; nortriptyline ; tyramine ; noradrenaline uptake ; clinical trial
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary This report describes a phase I clinical trial of a new tricyclic imipramine analogue (Leo 640) with a hydrogen atom in one of the N-methylgroups substituted by a p-chlorobensoyl. To get an objective assessment of the effects of Leo 640 we utilized the fact that tricyclic antidepressants inhibit the uptake of tyramine (thereby blocking its indirect sympathomimetic effects) and noradrenaline into peripheral adrenergic nerves. Dose-response (systolic pressor effects) curves for tyramine (TA) were established before and during treatment with Leo 640. Adrenergic nerves from the rat iris were incubated in the patient's plasma drawn immediately before the TA tests. The inhibitory effect of the endogenous plasma level of Leo 640 (and/or its metabolites) on the uptake of3H-noradrenaline (3H-NA) in these nerves was then determined. — Leo 640 was given orally in successively increasing doses (up to 1.1–5.6 mg/kg/day) to fifteen patients with various forms of depression. The duration of treatment was usually 3–4 weeks. Leo 640 caused a blockade of TA- pressor responses. Plasma of all treated patients inhibited the uptake of3H-NA in the rat iris. The results in the two tests were reasonably well correlated (p〈0.01). — The results in the TA- and “rat-iris” tests were compared with those obtained with nortriptyline (NT) in the same dose-range in nine other patients. In comparison with NT, Leo 640 had a more pronounced inhibitory effect on TA-responsesin vivo than of3H-NA uptake in adrenergic nervesin vitro. A possible explanation might be that Leo 640 has an α-receptor blocking effect. — For both Leo 640 and NT, poor correlations were found between the doses (mg/kg) used and the objective effects, when different patients were compared, probably due to marked interindividual differences in pharmacokinetics. — It is concluded that the dose-range of Leo 640 should be similar to that of NT in terms of the effects onperipheral adrenergic neurons.
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  • 2
    Electronic Resource
    Electronic Resource
    Springer
    European journal of clinical pharmacology 6 (1973), S. 81-87 
    ISSN: 1432-1041
    Keywords: Neuroleptics ; tyramine ; noradrenaline uptake ; chlorpromazine ; thioridazine ; haloperidol ; nortriptyline
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology , Medicine
    Notes: Summary Two methods have recently been described for determining the effect of psychotropic drugs on noradrenergic nerves. Membrane pump blockade can be quantified by inhibition of uptake of3H-noradrenaline (NA) by rat irides incubated in drug-containing plasma. Tyramine, an indirectly acting sympathomimetic, produces a temporary rise in blood pressure after intravenous injection and may also be used to quantify the effect of drugs on adrenergic transmitter mechanisms in man. Patients taking the neuroleptics, chlorpromazine, thioridazine and haloperidol have been studied. Using these two methods, haloperidol had no effect on noradrenergic transmitter mechanisms. Thioridazine also had no effect on the NA membrane pump but produced slight receptor blockade. Chlorpromazine had an inhibitory effect on the NA uptake mechanism of the rat iris, both in model experiments and in plasma from patients. The blockade was less than that produced by nortriptyline. The results of the tyramine test were similar to those obtained after nortriptyline. The discrepancy is probably due to blockade of the NA receptor by chlorpromazine. The neuroleptic drugs appear to have in common the ability to produce blockade of central dopamine receptors and this has been proposed as the explanation of their antipsychotic effect. There is probably no simple relationship between the effects of these drugs on NA transmitter mechanisms and their antipsychotic effects. The widespread effects of chlorpromazine on monoamine transmitter mechanisms might, however, account for its continued popularity, often as the drug of choice, in treating psychoses, despite the introduction of many other neuroleptics.
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